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Part1 dental Amino Acid Metabolism 2012
- 2. OVERVIEW OF CENTRAL AMINO ACID METABOLISM ENVIRONMENT ORGANISM Ingested Diatary proteins 70-100g/d Bio- synthesis Body Proteins 35-200g/d AMINO ACIDS Nitrogen (NH3) Carbon skeletons (Keto- acids) Urea Degradation (required) 1 2 3 a b Purines Pyrimidines Porphyrins (heme) Niacin Neurotansmitters Polyamines c c Used for energy pyruvate α-ketoglutarate succinyl-CoA fumarate oxaloacetate acetoacetate acetyl CoA (glucogenic) (ketogenic) CO2 + Water
- 3. Metabolic Classification of the Amino Acids • Based on synthesis: Essential and Non-essential • Based on degradation (Fate): Glucogenic and Ketogenic Essential Amino Acids in Humans • Required in diet • Human is incapable of forming their requisite carbon skeleton Non-essential Amino Acids in Humans • Not required in diet • Can be formed from α-keto acids by transamination and subsequent reactions • Valine • Leucine • Isoleucine • Methionine • Phenylalanine •Tryptophan • Threonine •Histidine* • Lysine •Glycine •Alanine •Proline •Tyrosine* •Serine •Cysteine* •Glutamine •Asparagine •Glutamate •Aspartate •Arginine*
- 4. DEGRADATION (FATE) OF THE CARBON SKELETONS Carbon skeletons are used for energy. Glucogenic Amino Acids: degradead to TCA cycle intermediates Oxaloacetate, Fumarate,Succinyl CoA, α-ketoglutarate, or pyruvate (gluconeogensis). Ketogenic Amino Acids: degraded to acetyl CoA, acetoacetyl CoA, or acetoacetate ( form ketone bodies).
- 5. AMINO ACID DEGRADATION INTERMEDIATESAMINO ACID DEGRADATION INTERMEDIATES CO2 CO2 Pyruvate Acetyl-CoA Acetoacetate Citrate Isocitrate -ketoglutarate Succinyl-CoA Fumarate Oxaloacetate Citric Acid Cycle CO2 Glucose Ala Ser Cys Thr* Gly Trp* Ile* Leu• Lys• Thr* Leu• Trp* Lys• Tyr* Phe* Asn Asp Asp Phe* Tyr* Ile* Met Val Arg His Glu Pro Gln Glucogenic Ketogenic * Both Glucogenic and Ketogenic • Purely Ketogenic PEP Malate Succinate
- 6. Incorporation of NH4 + Into Organic Compounds 1) NH4 + + HCO3 - + 2 ATP NH2CO2PO3 -2 + 2 ADP + Carbamoyl Phosphate Pi + 2 H+ 2) NH4 + + Carbamoyl Phosphate Synthetase I (CPS-I) Glutamate dehydrogenase O - O2CCH2CH2CCO 2 - -Ketoglutarate Glutamate NADP +NADPH + H+ NH3 + - O2CCH2CH2CHCO 2 - TCA Cycle Incorporation of NH4 + Into Organic Compounds (Cont.) NH3 + - O2CCH2CH2CHCO 2 - + NH4 + + 2 ATP NH3 +O H2NCCH2CH2CHCO 2 - Glutamine Glutamate Glutamine Synthetase Mg++ N of glutamine donated to other compounds in synthesis of purines, pyrimidines, and other amino acids 3)
- 7. Biosynthesis of Amino Acids *Transaminations: Amino Acid1 +α-Keto Acid2 Amino Acid2 +α-Keto Acid1 + O R-CCO 2 - Glutamate Pyridoxal phosphate (PLP)- Dependent Aminotransferase + α- Ketoglutarate Biosynthesis of Essential Amino Acids Their -ketoacids are not common intermediates (enzymes needed to form them are lacking) so transamination is not an option. Biosynthesis of Non-essential Amino Acids Transamination of -ketoacids that are available as common intermediates. (treatment of hyperamonemia) All (except Tyr) synthesized from the common intermediates synthesized in cell : • Pyruvate • Oxaloacetate • -ketoglutarate • 3-phosphoglycerate NH3 + - O2CCH2CH2CHCO 2 - NH2 R-CHCO 2 - O - O2CCH2CH2CCO 2 -
- 8. Transamination Reactions : One Step Pyruvate + AA Alanine + -ketoacid Oxaloacetate + AA Aspartate + -ketoacid -ketoglutarate + AA Glutamate + -ketoacid Transaminases: Equilibrate amino groups among -ketos. Require pyridoxal phosphte (PLP). Blood transaminases has a diagnostic value. (AST or GOT , ALT or GPT) All AAs, except Lys and Thr, can be transaminated. Most transaminases generate Glu or Asp. *ATP-dependent amidation of Glu, Asp: GLU + ATP + NH3 GLN + ADP + Pi By the nnzyme glutamine synthetase Where NH3 is toxic ; stored as Gln. Gln donates amino gps in many reactions ASP + ATP + GLN ASN + AMP + PPi + GLU By the enzyme Asparagine synthetase. Low in some cell tumor types. ( Asparaginase treatment ) .
- 9. Transaminations Glutamate -Ketoglutarate + + Pyruvate Alanine Glutamate -Ketoglutarate + + Oxaloacetate Aspartate Glutamate-Pyruvate Aminotransferase (Alanine Transferase ALT) Glutamate-Oxaloacetate Aminotransferase (Aspartate Transferase AST) Blood levels of these aminotransferases, also called transaminases, are important indicators of liver disease
- 10. AAMMIINNOO AACCIIDD CCAATTAABBOOLLIISSMM AA.. NNiittrrooggeenn ((NNHH3)) H2N C O NH2 urea Most terrestrial land animals convert excess nitrogen to urea, prior to excreting it. Urea is less toxic than ammonia. The Urea Cycle occurs mainly in liver excreted by kidney. The 2 nitrogen atoms of urea enter the Urea Cycle as NH3 (produced mainly via Glutamate Dehydrogenase) and as the amino N of aspartate. The NH3 and HCO3 (carbonyl C) that will be part of urea are incorporated first into carbamoyl phosphate.
- 11. Carbamoyl Phosphate Synthetase is the committed step of the Urea Cycle, and is subject to regulation. H2N C OPO3 2 O HCO3 + NH3 + 2 ATP + 2 ADP + Pi Carbamoyl Phosphate Synthetase carbamoyl phosphate N H C COO CH2 CH2 COO H CH3C O N-acetylglutamate H3N+ C COO CH2 CH2 COO H glutamate (Glu) Carbamoyl Phosphate Synthetase has an absolute requirement for an allosteric activator N-acetylglutamate. This derivative of glutamate is synthesized from acetyl-CoA & glutamate when cellular [glutamate] is high, signaling an excess of free amino acids due to protein breakdown or dietary intake.
- 12. H2N C OPO3 2 O CH2 CH2 CH2 HC COO NH3 + NH3 + CH2 CH2 CH2 HC COO NH3 + NH CO NH2 COO CH2 HC COO NH2 CH2 CH2 CH2 HC COO NH3 + NH C NH2 + COO CH2 HC COO H N AMP + PPi ATP CH2 CH2 CH2 HC COO NH3 + NH C NH2 + H2N COO HC CH COO C NH2H2N O H2O Pi ornithine urea citrulline aspartate arginino- succinate fumarate arginine carbamoyl phosphate Urea Cycle 1 2 3 4 Urea Cycle -Enzymes in mitochondria: 1. Ornithine Trans- carbamylase -Enzymes in cytosol: 2. Arginino- Succinate Synthetase 3. Arginino- succinase 4. Arginase.
- 13. Fumarate is converted to oxaloacetate via Krebs Cycle. Oxaloacetate is converted to aspartate via transamination (e.g., from glutamate). Aspartate then reenters Urea Cycle, carrying an amino group derived from another amino acid. aspartate -ketoglutarate oxaloacetate glutamate Aminotransferase (Transaminase) COO CH2 CH2 C COO O COO CH2 HC COO NH3 + COO CH2 CH2 HC COO NH3 + COO CH2 C COO O+ +
- 14. Hereditary deficiency of any of the Urea Cycle enzymes leads to hyperammonemia - elevated [ammonia] in blood. Total lack of any Urea Cycle enzyme is lethal. Elevated ammonia is toxic, especially to the brain. If not treated immediately after birth, severe mental retardation results. Postulated mechanisms for toxicity of high [ammonia]: 1. High [NH3] would drive Glutamine Synthetase: glutamate + ATP + NH3 glutamine + ADP + Pi This would deplete glutamate – a neurotransmitter & precursor for synthesis of the neurotransmitter GABA (later) . 2. Depletion of glutamate & high ammonia level would drive Glutamate Dehydrogenase reaction to reverse: glutamate + NAD(P)+ α-ketoglutarate + NAD(P)H + NH4 + The resulting depletion of α-ketoglutarate, an essential Krebs Cycle intermediate, could impair energy metabolism in the brain. Deficiencies related to Urea Cycle Carbamoyl Phosphate Synthetase Deficiency and N-acetylglutamate synthetase Deficiency Ornithine Transcarbamoylase Dificiency Argininosuccinate Synthetase and Lyase Deficiencies Arginase Deficiency
- 15. • Blood Urea Nitrogen (BUN) • Normal range: 7-18 mg./dL Elevated in ↑amino acid catabolism ↑Glutamate ↑N-acetylglutamate ↑CPS-1 activation Elevated in renal insufficiency Decreased in hepatic failure